A new approach to total synthesis of protoberberine and benzophenanthridine alkaloids is being investigated in which the condensation of certain Schiff bases with homophthalic anhydrides is the convergent step in the production of key intermediates which can then be transformed into a variety of naturally occurring metabolites within these classes by known methods. Specific objectives within these classes have been selected in view of previously demonstrated antileukemic activities. Compounds prepared in this study will be tested for antileukemic activity in mammalian cell culture as well as in in vivo tumor systems. Our more immediate objectives include synthesis of 13-methyltetrahydroprotoberberines, which offer the unique opportunity to control the conformation of the quinolizidine system by manipulation of the relative configuration at C-13 and C-14. This should allow us to test the hypothesis that a planar conformation is necessary for cytotoxicity, which would be required for an intercalation mechanism. We also hope to correlate the results of these studies with investigation of DNA binding. In case an intercalation mechanism is established, we will then incorporate the features of a bifunctional alkylating agent into the protoberberine system in an attempt to cross-link the complementary strands of DNA, thereby inhibiting replication.